Abstract

Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide which activates the
NOP receptor. N/OFQ exerts an inhibitory control on locomotion through inhibition of
dopamine (DA) neurons located in the substantia nigra (SN), which degenerate in
Parkinson’s disease (PD). In the present study, we demonstrated that NOP receptor
antagonists facilitated and inhibited motor behavior in 1-methyl-4-phenyl-1,2,5,6-
tetrahydropyridine (MPTP)-treated mice and nonhuman primates depending on dose. In
naïve mice, we found that dual response to NOP receptor antagonists was DAdependent
and mediated by D2 postsynaptic (facilitation) and D2 presynaptic receptors
(inhibition). Consistently, inhibition induced by high doses of NOP receptor antagonists
in MPTP-treated mice was reversed by D2 receptor blockade, leading to a widening of
their therapeutic window. Evidence that endogenous N/OFQ not only sustains
symptoms but also contributes to neurodegeneration in PD was also provided. In fact,
NOP receptor knockout mice were found to be partially resistant against MPTP-induced
loss of nigral DA cells. In order to understand the mechanisms underlying motor effects
of endogenous N/OFQ, we investigated the role of nigral NOP receptors in the control
of motor cortex (M1) output. Motor inhibition induced by exogenous N/OFQ was
associated with reduction in M1 excitability while the opposite was true for motor
facilitation induced by NOP receptor antagonists. Finally, we investigated M1
reorganization in parkinsonian conditions and found that M1 excitability was decreased
after 6-OHDA lesioning in rats. We concluded that endogenous N/OFQ controls motor
activity via NOP receptors located in SN and through modulation of DA transmission,
leading to changes in activity of the basal ganglia-thalamo-cortical pathway and M1
output. Moreover, we provide evidence that NOP receptor antagonists may represent a
novel approach for symptomatic and neuroprotective therapy of PD.